The research proposed herein envisions the design and synthesis of new benzodiazepine receptor ligands through application of the current state of knowledge regarding structure-activity and structure-affinity correlations and the proposed models for receptor-ligand interactions. A particular aim of the project is to identify new and potent receptor ligands that will show specificity in their receptor interaction and in the pharmacological response they elicit. A prime focus of the research will be to identify ligands that will show a pure antagonist profile or a partial agonist profile since such compounds may show promise as drugs for the treatment of benzodiazepine dependence or for the prevention of the development of benzodiazepine dependence. The candidate molecules to by synthesized will be evaluated for their receptor binding affinity in vitro using radioligand assay systems, and for activity agonist/antagonist/inverse agonist profile by in vitro and in vivo methods. Promising compounds will be further evaluated in animal models for their effectiveness as a drug for the treatment of dependence and prevention of benzodiazepine withdrawal symptoms. These evaluations will be carried out in collaboration with other laboratories that are currently involved in such studies. In the design of newer ligands the proposed research will focus on target structures related to the antagonist drug Flumazenil possessing the imidazobenzodiazepinone framework. Proposed targets include the selective functionalization of the basic framework as well as radical template modifications based on sound medicinal chemistry principles and drug design concepts. This comprehensive investigation is expected to lead to the discovery and development of useful drug entities. Moreover, the study of structural and physicochemical properties of the ligands and correlations with their affinity and activity profiles using computer-aided modeling techniques is expected to advance significantly the current state of knowledge regarding the receptor-ligand interactions and aid in the development of new stereochemical models for benzodiazepine ligand-receptor interactions.